The biological behavior of gastric enterochromaffin (ECL) cell tumors remains an enigma and their clinical management a source of controversy and concern. As a result, surgical management is often disparate and based upon relatively arbitrary concepts (size, primary lesions, and number of lymph nodes) and the inability to define whether the lesions are simply hyperplastic cell aggregates that are gastrin-dependent for their growth or gastrin-autonomous neoplastic cells. The aims of this grant are to identify molecular markers that can be utilized to assess whether the ECL cell is gastrin-responsive or when the lesion has become gastrin-autonomous. A unique rodent model (Mastomys) has been developed in our laboratory to investigate ECL cell tumor biology. This rodent is unique in being the only known model of rapid (< 4 months) ECL cell tumor transformation. Numerous studies have indicated that its gastric carcinoid lesion is similar to that of human disease. Our preliminary data utilizing a number of molecular strategies in ECL cell tissue from rats, Mastomys and human demonstrate several conserved gene alterations particularly associated with AP-1 activity. Our hypothesis is that a biological rationale for surgical therapy for ECL cell carcinoids may be derived from studying and defining the evolution of ECL cell proliferation and neoplastic transformation in the Mastomys and applying these findings to humans. The most promising initial gene target pathway is AP-1 transcription. The aims of the proposal are 1) identify whether fos/jun expression is a marker of ECL cell autonomy in Mastomys exposed to variable periods of hypergastrinemia, 2) define the gene pattern expression pathways associated with gastrin autonomy in the ECL cell using gene chip technology to examine alterations in gene expression as the ECL cell converts from normal to gastrin dependent and gastrin-autonomous neoplasia, 3) examine the human relevance of gastrin autonomous genes using tissue microarray technology. A pre-operative determination of the neoplastic ECL cell gene expression relating to gastrin responsiveness will improve the rationale for therapeutic gastric or antral resection.